BRPI0922736B1 - 11-(2-PYRROLIDIN-1-YL-ETOXY)-14,19-DIOXA5,7,26-TRIAZA-TETRACYCLE CITRATE SALT [19.3.1.1(2,6).1(8,12)]HEPTACOSA1( 25),2(26),3,5,8,10,12(27),16,21,23-DECAENE, PHARMACEUTICAL COMPOSITION COMPRISING THIS AND USE THEREOF - Google Patents

Abstract

11-(2-PYRROLIDIN-1-YL-ETOXY)-14,19-DIOXA-5,7,26-TRIAZA-TETRACYCLE CITRATE SALT[19.3.1.1(2,6).1(8,12)] HEPTACOSA-1(25),2(26),3,5,8,10,12(27),16,21,23-DECAENE The present invention relates to certain salts of an 11-(2-pyrrolidin- 1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26) ,3,5,8,10,12(27),16,21,23-decaene (Compound I) in which the presence of improved properties was found. In particular the present invention relates to the citrate salt of this compound. The invention also relates to pharmaceutical compositions containing the citrate salt and methods of using the citrate salt in the treatment of certain medical conditions. Compound I

Description

FIELD

[001]The present invention relates to the citrate salt of 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2, 6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene. Furthermore, the present invention relates to pharmaceutical compositions containing the citrate salt and methods of using the salt in the treatment of certain medical conditions.

FUNDAMENTALS

Composto I[002]The Compound 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12) ]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (Compound I) was first described in PCT/SG2006/000352 and shows significant promise as a pharmaceutically active agent for the treatment of various medical conditions and clinical development of this compound is under way based on the activity profiles demonstrated by the compound.

Compound I

[003] In developing a drug suitable for mass production and acceptable usage levels, ultimately commercial activity of the drug against the target of interest is just one of the important variables that must be considered. For example, in formulating pharmaceutical compositions it is imperative that the pharmaceutically active substance be in a form that can be reliably reproduced in a commercial manufacturing process and that is sufficiently robust to withstand the conditions in which the pharmaceutically active substance is present. exposed.

[004] In a production sense it is important that during commercial manufacturing the manufacturing process of the pharmaceutically active substance is such that the same material is reproduced when the same production conditions are used. In addition, it is desirable that the pharmaceutically active substance exists in a solid form, where small changes to the conditions of production do not lead to large changes in the solid form of the pharmaceutically active substance produced. For example, it is important that the manufacturing process produces materials with the same crystalline properties, on a reliable basis, and also produces material with the same level of hydration.

[005] In addition, it is important that the pharmaceutically active substance is stable to both degradation, hygroscopicity and subsequent changes to its solid form. This is important to facilitate the incorporation of the pharmaceutically active substance into pharmaceutical formulations. If the pharmaceutically active substance is hygroscopic ("rough") in the sense that it absorbs water (either slowly or over time), it is nearly impossible to reliably formulate the pharmaceutically active substance into a drug as well as the The amount of substance to be added to provide the same dosage can vary greatly depending on the degree of hydration. In addition, variations in hydration or solid form ("polymorphism") can lead to changes in physicochemical properties, such as solubility or dissolution rate, which can lead to inconsistent oral absorption in a patient.

[006] Thus, the chemical stability, solid state stability, and "shelf life" of the pharmaceutically active substance are very important factors. In an ideal situation the pharmaceutically active substance and all compositions that contain it should be able to be effectively stored for significant periods of time, without demonstrating a significant change in the physicochemical characteristics of the active substance, such as its activity, moisture content, solubility characteristics, continuous form and the like.

[007]Regarding 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12) )]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene, initial studies were performed on the hydrochloride salt, and indicated that the polymorphism was prevalent with compound being found to adopt more than one crystalline form depending on production conditions. In addition, it was observed that the moisture content and the ratio of polymorphs varied from batch to batch, even when production conditions remained constant. These batch-to-batch inconsistencies and the hygroscopicity exhibited made the hydrochloride salt less commercially desirable.

[008] Consequently it would be desirable to develop a salt or salts of 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6) .1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene that overcome or improve one or more of the above problems identified.

SUMMARY

[009] The present invention provides a citrate salt (citric acid salt) of 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3. 1.1(2,6).1(8,12)] heptacosa-1(25),2(26),3.5, 8,10,12(27),16,21,23-decaene.

[0010] In some embodiments the salt is crystalline.

[0011]In some embodiments the salt is 1:1 citrate salt. In some embodiments the citrate salt shows on X-ray diffraction a peak in the 2theta scale at 22.4°±0.5°.

[0012]In some embodiments the citrate salt shows in X-ray diffraction peaks in the 2theta scale at 10.2°±0.5° and 15.7°±0.5°.

[0013]In some embodiments the citrate salt shows in X-ray diffraction at least four peaks on the 2theta scale selected from the group consisting of 7.8°±0.5°, 10.2°±0.5°, 14.2°±0.5°, 15.7° ±0.5°, 16.8°±0.5°, 21.4°±0.5°, and 22.4°±0.5°.

[0014]In some embodiments the citrate salt shows in X-ray diffraction at least 6 peaks on the 2theta scale selected from the group consisting of 7.8°±0.5°, 10.2°±0.5°, 14.2°±0.5°, 15.7° ±0.5°, 16.8°±0.5°, 21.4°±0.5°, and 22.4°±0.5°.

[0015]In some embodiments the citrate salt shows in X-ray diffraction peaks in the 2theta scale of 7.8°±0.5°, 10.2°±0.5°, 14.2°±0.5°, 15.7°±0.5°, 16.8°±0.5° , 21.4°±0.5°, and 22.4°±0.5°.

[0016]In some embodiments the citrate salt also shows in X-ray diffraction peaks in the 2theta scale of 7.2°±0.5°, 10.9°±0.5°, 17.1°±0.5°, 17.6°±0.5°, 18.5°±0.5° °, 18.7°±0.5°, 20.7°±0.5°, 23.1°±0.5°, 23.3°±0.5°, 24.2°±0.5°, 25.1°±0.5°, 25.8°±0.5°, 26.2°±0.5°, 26.9°±0.5°, 27.5°±0.5°, 28.7°±0.5°, 29.3°±0.5°, 31.0°±0.5°, 32.4°±0.5°, 37.3°±0.5°, 38.6°±0.5°, 39.9° ±0.5° and 41.6°±0.5°.

[0017] The present invention also provides a pharmaceutical composition comprising a salt as described above.

[0018] In another embodiment the present invention provides a method of treating or preventing a proliferative disorder comprising administering a therapeutically effective amount of a salt of the invention to a patient in need thereof. In some embodiments the proliferative disorder is cancer.

[0019] In another embodiment the present invention provides the use of a salt of the invention in the treatment of a proliferative disorder. In some embodiments the proliferative disorder is cancer.

[0020] In another embodiment the present invention provides the use of a salt of the invention in the manufacture of a medicament for the treatment of a proliferative disorder. In some embodiments the proliferative disorder is cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021]Figure 1 shows the X-Ray Energy Diffraction Batch Diffractogram (XRPD) HCl 1: low resolution trace (C2, above) and high resolution trace (D5000, below).

[0022]Figure 2 shows the results of Differential Scanning Calorimetry (DSC) (top) and thermal gravimetric analysis (TGA) (bottom) of Batch HCl 1.

[0023]Figure 3 shows the results of Gravimetric Vapor Sorption (GVS) of Batch HCl 1.

[0024]Figure 4 shows the pre- and post-GVS HCl 1 Batch XRPD Diffractograms.

[0025]Figure 5 shows the XRPD Batch HCl 2 Diffractogram.

[0026]Figure 6 shows the TGA (top) and DSC (bottom) results of Batch HCl 2.

[0027]Figure 7 shows the XRPD Batch HCl 3 Diffractogram.

[0028]Figure 8 shows the TGA (top) and DSC (bottom) results of Batch HCl 3.

[0029]Figure 9 shows the high resolution XRPD Diffractogram of Batch HCl 4.

[0030]Figure 10 shows the DSC (top) and TGA (bottom) results of Batch HCl 4.

[0031]Figure 11 shows the SGS results of Batch HCl 4.

[0032]Figure 12 shows the XRPD Batch Diffractogram of HCl 5 (2 conditions).

[0033]Figure 13 shows the results of the DSC Thermogram of Batch HCl 5 (prepared from Ethanol).

[0034]Figure 14 shows the XRPD Batch Diffractogram of HCl 6: low resolution trace (C2, above) and high resolution trace (D5000, below).

[0035]Figure 15 shows the TGA (top) and DSC (bottom) results of Batch HCl 6.

[0036]Figure 16 shows the SGS results of Batch HCl 6.

[0037]Figure 17 shows high resolution X-ray diffraction patterns (D5000) of Citrates from Batch 1, 2, 3 and 4.

[0038]Figure 18 shows the TGA (top) and DSC (bottom) results of Batch 1 Citrate.

[0039]Figure 19 shows the TGA (top) and DSC (bottom) results of Batch 2 Citrate.

[0040]Figure 20 shows the TGA (top) and DSC (bottom) results of Batch Citrate 3.

[0041]Figure 21 shows the TGA (top) and DSC (bottom) results of Batch 4 Citrate.

[0042]Figure 22 shows the variable temperature X-ray diffraction pattern of Batch 1 Citrate.

[0043]Figures 23 and 24 show the GVS experiment and post GVS XRPD spectra, respectively, for Batch 1 Citrate.

[0044]Figures 25, 26, 27, 28 and 29 show the high resolution X-ray diffraction pattern of Batch Citrate from Batch 2, 3, 4, 5 and 6 respectively, recorded on an instrument other than that of figure 17.

[0045]Figure 30 shows the X-ray diffraction pattern of material A of the citrate salt group both before and after being kept for one week in the humidity chamber at 60°C and 96%RH.

DETAILED DESCRIPTION

[0046]As stated above it will now be found that certain salts of 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6 ).1(8,12) heptacosa 1(25), 2(26),3,5,8,10,12(27),16,21,23-decaene exist as the only robust polymorphs. In particular the present Applicants have found that the citrate salt (citric acid salt) of this compound exists as a single polymorph.

Ácido Cítrico[0047]While it is assumed that the structure of citric acid will be apparent to one skilled in the art, in order to avoid any uncertainty the structure is shown below.

Citric acid

[0048]Initial studies of compound I involved analysis of the hydrochloride salt. It was found summarized in Table 1 below, that the initially prepared hydrochloride salt produced an inconsistent solid form with variability consistent across the DSC, TGA, GVS and XRPD pattern (see Figures 1 to 16). Table 1: Solid Form Analysis Tabulation of Various Hydrochloride Salts of Compound 1

[0049] As can be seen from the table despite the same production conditions (batch 1 to 3) being used, there was a wide variety of solid forms identified in the analysis of batches of hydrochloride salt 6 indicating that with this salt there is a high degree of polymorphism.

[0050] The XRPD for the Batch sample of HCl 1 (see table 1) is shown in figure 1. This diffractogram indicated that this batch has relatively low levels of crystallinity and an amorphous halo indicating a mixture of phases. Thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC) for the Batch sample of HCl 1 is shown in figure 2. The TGA shows a two-stage weight loss totaling 4.5% at 100°C which equates to 1.4 water equivalents. This corresponds well to the two endotherms seen in DSC with onsets at 40°C and 88°C, respectively. This is most likely a loss of water from the sample since no solvent in the process was observed in 1H NMR. Then follows an exothermic event starting at 141°C which would most likely be a phase change to a new solid form followed by a final endothermic event, probably a melting, starting at 238°C followed by decomposition. These physical changes can be visually seen on a hot stage microscopy video.

[0051]The GVS results for the Batch HCl 1 sample are shown in Figure 3. The example shows an initial adsorption of water in the initial adsorption cycle of 5.5% to 90% RH. The sample then loses 5% mass going to dryness and then regains mass by 2% going to 40% RH for a total gain of 2%. This 2% gain would bring the water content up to 6.5%, which corresponds to a dihydrate. The example appears to be a partially dehydrated hydrate which, once exposed to a sufficiently high level of water, gains moisture and then permanently holds onto it during the GVS experiment. To determine if there was a change in the solid shape of the material after the GVS experiment an XRPD diffractogram was obtained and is shown in Figure 4. The GVS after X-ray diffractogram is similar to the starting material, but with more intense peaks. In addition, some minor peaks in the original diffractogram (about 8.5 and 15.5 2theta) disappeared. It is likely that the material subjected to the GVS experiment contained more than one crystalline phase (shape) and that one of the shapes changed under exposure to high humidity.

[0052]The XRPD spectrum of the Batch of HCl 2 is shown in figure 5 and as can be seen there is a low correlation with the XRPD obtained with the Batch of HCl 1. The TGA and DSC spectra of the Batch of HCl 2 are shown in Figure 6 and have some similarities, but are not identical, to Batch HCl 1. Batch HCl 2 lost 5.6% water in the first stage of TGA until decomposition at 260°C. This water loss represents 1.67 water equivalent. The DSC spectrum shows the same three thermal events as seen with Batch HCl 1, however the two sets of data are clearly not the same.

[0053]The XRPD spectrum of the Batch of HCl 3 is shown in Figure 7 and does not agree well with the batches of HCl 1 or HCl 2. The XRPD of the Batch of HCl 3 was quite complex, with much more reflections than other batches and a additional reflection in 2θ of 6.7 not present in other batches. The TGA and DSC spectra of Batch HCl 3 are shown in figure 8. The sample lost 1.5% water in the first TGA stage, then another 1.97% loss, possibly solvent, at 165° C until decomposition at 260 °C. This water loss represents 0.5 equivalent of water, less than 1.1 equivalent (3.79%), indicated by the Karl-Fischer analysis. One possible reason for this is that a higher temperature is required to release the water held in the structure through dehydration, a small expansion of the latex that will release the water held back, or a change in the crystal structure. The total weight lost in TGA is 3.4%. The DSC spectrum shows the same three thermal events as seen with Batch HCl 1 and 2, but with an additional endothermic event at 200 °C, probably a desolvation.

[0054]In order to investigate the behavior observed above, the HCl salt was recrystallized by refluxing acetonitrile/water to produce 79 mg of a yellow powder, Batch HCl 4. This was analyzed by XRPD, TGA and DSC and the data are shown in Figures 9 and 10. This material was shown to be a single, isolated polymorphic form of the HCl salt (hereinafter referred to as "Group 1"). As an alternative to recrystallization, direct formation of the Group 1 material from the free base and aqueous acid can also be performed. Figure 9, which shows the XRPD spectrum of Batch HCl 4 (Group 1) does not agree with any of the batches described above. Figure 10 shows the TGA and DSC spectra of Batch HCl 4 indicating that the sample loses 6.5% of its mass between room temperature and 108 °C. Two equivalents of water are equivalent to 6.58%. This correlates well with the broad endotherm seen in the DSC (onset = 76 °C). The DSC then shows an exothermic phase change (start = 148 °C), then goes on to show a final endotherm (start 222 °C).

[0055]GVS analysis was performed and the data are shown in Figure 11. The sample showed very little water absorption gaining only 1.6% by mass going from 40% RH to 90% RH. The sample lost 2.8% in mass going from 90% RH to dryness. The sample was analyzed by XRPD post GVS. The shape of the sample has not changed (data not shown).

[0056] A second, different and isolable polymorphic form (Batch HCl 5) can be prepared when the HCl salt is synthesized from the amorphous HCl salt via a "maturation" process. In this process a small amount of the amorphous salt (10mg) was treated with 10 or 20 volumes of methanol or ethanol in a flask. The vials were capped and placed in a maturation chamber that cycled from room temperature to 50 °C, with four hours spent in each condition. After approximately 18 hours the samples were filtered and analyzed. This material was shown to be a unique polymorphic form of HCl salt different from the Group 1 material (hereinafter referred to as "Group 2"). Figure 12 shows XRPD diffractograms for samples prepared in ethanol (20 vols, top) and methanol (10 vols, below). Although there are small differences between the samples, it is evident that these data are quite different from other batches described in this document. Figure 13 shows the DSC of the sample prepared in ethanol, which is clearly much more complex than other batches.

[0057] A third, different and isolable polymorphic form, Batch HCl 6, can be prepared when the HCl salt is synthesized from the free base in acetone or in alcoholic solvents with methanol or aqueous HCl. Figure 14 shows the XRPD diffractogram, recorded on low and high resolution instruments, and again it is different from the other batches described in this document. Surprisingly, the DSC and TGA spectra shown in Figure 15 are very simple, with very little weight loss recorded in TGA until degradation occurs around 240 °C and also no thermal events in DSC until melting and decomposition. This material has been shown to be a unique polymorphic form of HCl salt different from that of group 1 and 2 materials (hereinafter referred to as "Group 3"). In the GVS (Figure 16), the sample showed very little water sorption, gaining only 1.6% by mass, going from 40% RH to 90% RH. The sample lost 2.4% by mass going from 90% RH to dryness. The sample was analyzed by GVS post XRPD. The shape of the sample was not changed after the experiment (data not shown). Both the HCl Batch 4 and 6 GVS experiments (groups 1 and 3) were somewhat similar to each other, but different from the HCl Batch 1, further underscoring the variable nature of the HCl salt.

[0058]The group three material has been stressed under conditions that can cause it to convert to the group one material or, indeed, another polymorphic or hydrated form. Thus, samples were stored at 40 °C / 75% RH and also at 60 °C / 96% RH and analyzed at regular intervals by XRPD. The results are summarized in Table 2. Table 2: Tabulation of Stress Tests in Clorid rat in Group 3

[0059]From the XRPD data (not shown), it appears that the group three material can be made into a group one material at elevated temperatures and humidity. This would have implications if group three material were chosen as the preferred form for production, as it would need to be produced in a controlled manner and any post-production manipulations, such as the formulation method, would need to be controlled to ensure that no it would be possible to convert to group one material.

[0060] Briefly, the processes employed to prepare and purify 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1( 2,6).1(8,12)] heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene do not adequately control the polymorphic form of the compound as well as there is an observed batch-to-batch variation. Despite careful work to identify three different apparently isolatable solid forms (Batch HCl 4-6) it is quite clear that the larger-scale batches (HCl 1-3) do not match any of these reference standards. Batch HCl 1 and 3 are mixtures of both Group 1 and 3 forms with different amounts of amorphous content. Batch HCl 2 is quite close to Group 1, but unfortunately contains other unexplained peaks in the XRPD pattern. Furthermore, even when a single polymorph has been produced (batches 4-6), they still show significant water absorption (typically up to 1.6%), which makes their use in pharmaceutical formulations difficult to ensure consistent dosing. Furthermore, the most promising of the hydrochloride salts (Batch HCl 6 - group 3) from the standpoint of DSC analysis was found to convert to other polymorphic forms under stress, as discussed above, indicating that this is not a stable polymorph.

[0061]As a result of the unacceptable variability observed with the hydrochloride salt, as discussed above an alternative robust solid form was required. Further discovery effort has identified the citrate salt as being such a robust solid form. Table 3 lists the citrate salt batches prepared and analyzed.

[0062] The analysis of the different batches of the citrate salt referred to in the table above demonstrated remarkable consistency as a single polymorph.

[0063]Figure 17 shows the high resolution X-ray diffraction pattern (D5000) of Citrates from batches 1, 2, 3 and 4 with Citrate 1 used as a reference standard. It is quite clear that the batches are very similar indeed and essentially identical for the purposes of establishing solid form. A complete list of all observed peaks is presented in Table 5.

[0064] Figures 18, 19, 20 and 21 show TGA (upper) and DSC (lower) spectra for batches of Citrate of 1, 2, 3 and 4, respectively. Gravimetric thermal analysis clearly demonstrates that citrate salts show no weight loss until they melt with decomposition at 180 °C. This indicates the overall temperature stability and robust nature of the citrate salt and also that it is generally not hygroscopic. In addition, inspection of the differential scanning calorimetry scheme indicates that no other events (phase changes, etc.) are evident for these salts. It is also clear from these data that the batches are essentially identical in their thermal profiles.

[0065]Figure 22 shows the variable temperature X-ray diffraction pattern of Citrate Batch 1. With reference to the variable temperature X-ray diffraction patterns showed that it is noticeable that there is no change regardless of the temperature of the experiment, indicating once again the robust nature of the citrate salt. Furthermore, figures 23 and 24 show the GVS experiment and post GVS XRPD spectra, respectively. The data indicate that citrate batch 1 also has low hygroscopicity, and no significant amount of water (less than 0.8%) is taken up between 0 and 90% RH. There is no change in the XRPD pattern before and after the GVS experiment.

[0066] Figures 25, 26, 27, 28 and 29 show the high resolution X-ray diffraction pattern of batches of Citrate 2, 3, 4, 5 and 6, respectively, recorded on a different instrument from Figure 17. This data is of very good resolution with the expansion of the y-axis peaks relative to Figure 17, however clearly the reflections are occurring at essentially identical 2theta and relative intensities to other XRPD data present here.

[0067] In order to determine the polymorphism propensity for the citrate salt, the group A material was matured in 27 different solvents. A small amount of suspended solids was slurried with the corresponding solvent (see Table 4) and stored in the incubator and subjected to 4h heating/cooling cycles at 50 °C/t for 24h. The solvents were removed under vacuum, and the remaining solid analyzed by XRPD. In all cases, only one solid form was identified. Table 4: Results of solids analysis after maturation studies

[0068]The stability of the citrate salt group A material was tested under harsher conditions, when the samples were kept for one week in a humidity chamber at 60°C and 96% RH. Figure 30 shows that no change was observed in the crystal pattern even under these conditions. Table 5: List of significant X-ray diffraction peaks for the citrate salt (Batch 6 Citrate with 2theta bands derived from Batch 2-5 Citrate)

[0069] As can be seen the citrate salt can be characterized by showing in X-ray diffraction a peak in the 2theta scale at 22.4°±0.5°.

[0070] In some embodiments the citrate salt may be further characterized by showing in X-ray diffraction peaks in the 2theta scale at 10.2°±0.5° and 15.7°±0.5°.

[0071]In some embodiments the citrate salt may be further characterized by showing in X-ray diffraction at least four peaks on the 2theta scale selected from the group consisting of 7.8°±0.5°, 10.2°±0.5°, 14.2°±0.5° °, 15.7°±0.5°, 16.8°±0.5°, 21.4°±0.5°, and 22.4°±0.5°.

[0072]In some embodiments the citrate salt may be further characterized by showing in X-ray diffraction at least 6 peaks on the 2theta scale selected from the group consisting of 7.8°±0.5°, 10.2°±0.5°, 14.2°±0.5° °, 15.7°±0.5°, 16.8°±0.5°, 21.4°±0.5°, and 22.4°±0.5°.

[0073]In some embodiments the citrate salt may be further characterized by showing in X-ray diffraction peaks in the 2theta scale at 7.8°±0.5°, 10.2°±0.5°, 14.2°±0.5°, 15.7°±0.5°, 16.8° °±0.5°, 21.4°±0.5°, and 22.4°±0.5°.

[0074]In some embodiments the citrate salt may be further characterized by showing in X-ray diffraction peaks in the 2theta scale at 10.9°±0.5°, 17.1°±0.5°, 23.3°±0.5°, 25.1°±0.5°, 25.8° °±0.5°, and 27.5°±0.5°.

[0075]While the peaks discussed above are the characteristic peaks, the citrate salt may also show in X-ray diffraction peaks in the 2theta scale at 7.2°±0.5°, 17.6°±0.5°, 18.5°±0.5°, 18.7° ±0.5°, 20.7°±0.5°, 23.1°±0.5°, 24.2°±0.5°, 26.2°±0.5°, 26.9°±0.5°, 28.7°±0.5°, 29.3°±0.5°, 31.0°±0.5° °, 32.4°±0.5°, 37.3°±0.5°, 38.6°±0.5°, 39.9°±0.5° and 41.6°±0.5°.

[0076] As will be appreciated by one versed in the field of relative diffraction intensities they can vary depending on a number of factors such as the sample preparation method and the type of instrument used. Furthermore, in certain cases, some of the above-mentioned peaks may not be detectable.

[0077] The salt of the present invention can be produced by reacting the free base of compounds (I) with a suitable form of citric acid in a suitable solvent and recovering the resulting salt reaction mixture after precipitation, crystallization and evaporation.

[0078] The reaction to form the salt can be carried out in any non-interfering solvent or mixture of solvents, in which the free base has adequate solubility. Examples of suitable solvents of this type include tetrahydrofuran, toluene and water. The process typically involves dissolving the free base in the appropriate solvent at elevated temperatures, such as greater than 20°C. In some embodiments, for example tetrahydrofuran, the free base is dissolved in the solvent at a temperature of approximately 65°C. In some embodiments, for example water, the free base is dissolved in the solvent at a temperature of approximately 90°C.

[0079]Once the free base has been dissolved in the appropriate solvent, then the process involves adding an appropriate amount of acid. The amount of acid can vary, although normally the amount of acid used is a stoichiometric equivalent or a slight stoichiometric excess. Following acid addition the process then normally involves stirring the reaction mixture at the addition temperature for a period of one hour followed by cooling the reaction mixture to a temperature below the reaction temperature to facilitate crystallization. Once the desired level of crystal formation has occurred the crystals can be isolated by filtration and dried using standard means in the art.

[0080] Another embodiment of the present invention provides for the use of the salts of the invention in the treatment of proliferative disorders. The formulations and methodology for using compounds of this type and the disorders that can be treated so are as disclosed in PCT/SG2006/000352.

[0081] The present invention will now be described with reference to the following non-limiting examples. Hydrochloride salts were prepared as discussed above by comparative examples and analyzed similarly. Example 1 Formation of the hydrochloride salt of compound I (Comparative example)

[0082]The free base 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12) )]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene was dissolved in dichloromethane, brought to reflux and treated with activated carbon. The mixture was filtered hot through a pad of celite and washed with dichloromethane. To the filtrate was added methanolic HCl and the mixture was stirred at 10-15 °C for 2-3 hours. The slurry was cooled to 5-10°C, filtered, washed with heptane and dried in a vacuum oven at 40-45°C to provide 11-(2-pyrrolidin-1-yl-ethoxy)-14 hydrochloride, 19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10, 12(27),16,21,23-decaene. Example 2 Formation of citrate salt

[0083]Compound I (50mg, 0.106mmol) was suspended in either THF or toluene (2mL), and gently heated to 65°C until it became a clear solution. The solution was then treated with 1 equivalent of citric acid, heated to 65°C for one hour and slowly cooled to 5°C overnight to facilitate crystallization. The crystals thus formed were then isolated by filtration. Example 3 Citrate salt formation

[0084]Compound 1 (50mg, 0.106mmol) was suspended in THF (2mL), and gently heated to 65°C until it became a clear solution. The solution was then treated with 1 equivalent of citric acid (as a solution in water), heated to 90°C for one hour and slowly cooled to 5°C overnight to facilitate crystallization. The crystals thus formed were then isolated by filtration. Example 4 Thermal gravimetric analysis and differential scanning calorimetry

[0085]Samples of both hydrochloride (comparative) and citrate salts were subjected to thermogravimetric analysis and differential scanning calorimetry under the following conditions. DSC data were collected on a TA Q2000 Instrument equipped with a 50 position autosampler. The instrument was calibrated for power and calibration temperature using certified indium. Usually 0.5-3 mg of each sample, in an aluminum pan with a perforated pin, was heated to 10 'C.min-1 from 25 °C to 270 °C.

[0086] A nitrogen purge of 50 mL.min-1 was maintained throughout the sample. Instrument control software was Thermal Advantage v4.6.6 and data were analyzed using Universal Analysis v4.3A. Alternatively, DSC data were collected on a Mettler DSC 823e equipped with a 50-position autosampler. The instrument was calibrated for energy and temperature using certified indium. Typically 0.5-3 mg of each sample, in a pin-hole aluminum pan, was heated to 10 °C.min-1 from 25 °C to 270 °C. Nitrogen removal at 50 ml.min-1 was maintained throughout the sample. The instrument control and data analysis software was STARv9.01.

[0087]TGA data were collected on a TA Q500 TGA instrument equipped with a position 16 autosampler. The instrument was temperature calibrated using certified Alumel. Typically 50-30 mg of each sample was placed in a pre-tared platinum crucible and DSC aluminum pan, and heated at 10 °C.min-1 from room temperature to 300 °C. Nitrogen removal at 60 ml.min-1 was maintained throughout the sample. Instrument control software was Thermal Advantage v4.6.6 and data were analyzed using Universal Analysis v4.3A. Alternatively, TGA data were collected on a Mettler 851e TGA / SDTA equipped with a 34 position autosampler. The instrument was temperature calibrated with certified indium. Typically 50-30 mg of each sample was placed in a pre-weighed aluminum crucible and heated at 10 °C.min-1 from room temperature to 300 °C. Nitrogen removal at 50 ml.min-1 was maintained throughout the sample. The instrument control and data analysis software was STARv9.01. The test results are shown in the above figures. Example 5 X-Ray Diffraction Analysis

[0088]Samples of both hydrochloride (comparative) and citrate salts were subjected to X-ray diffraction to determine the characteristic X-ray diffraction pattern. The conditions used were as follows: X-ray energy diffraction patterns were collected on a Siemens D5000 diffractometer with Cu Kα radiation (40kV, 40mA), θ-θ goniometer, V20 divergence and reception slits, a graphite monochromator and a secondary scintillometer. The instrument is verified for performance using a certified Corundum standard (NIST 1976). ambient conditions

[0089]Samples run under ambient conditions were prepared as flat plate specimens using the powder as received. Approximately 35 mg of the sample was carefully packaged into a cavity cut into polished, zero-bottom silicon wafers (510). The sample was rotated in its own plane during analysis. Data collection details are as follows: Angular Range: 2 to 42 °2θ Step Size: 0.05 °2θ Collection Time: 4 s.step-1.

[0090]Alternatively, X-ray energy diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for automatic sample positioning and a Histar two-dimensional area detector. X-ray optics consists of a single multilayer Gobel mirror coupled to a 0.3 mm pinhole collimator. The beam divergence, ie the effective size of the X-ray beam in the sample, was approximately 4 mm. The continuous θ-θ scanning mode was employed with a sample-detector distance of 20 cm which gives an effective range in the 2θ range of 3.2° - 29.7°. Typically, the sample would be exposed to the X-ray beam for 120 seconds.

[0091]Samples run under ambient conditions were prepared as flat plate specimens using the powder as received without grinding. About 1-2 mg of the sample was lightly pressed onto a glass slide to obtain a flat surface. non-ambient conditions

[0092]Samples run under non-ambient conditions were mounted on a silicon wafer with heat conductive compound. The sample was then heated to a suitable temperature at about 10 °C.min-1 and subsequently held isothermally for about 2 minutes before data collection began.

[0093] The X-ray diffraction patterns for the citrate salts are shown in the above figures. Example 6 X-ray diffraction variable temperature

[0094] In order to investigate the stability of samples of citrate salts X-ray dif- raction of variable temperature was performed. Thus, the salts were verified under X-ray diffraction conditions at a series of temperatures and the characteristic peaks determined. The results of each of the scans are shown in the figures above.

[0095] The details of specific embodiments described in the present invention are not to be construed as limitations. Various equivalents and modifications may be made without departing from the essence and scope of this invention, and it is understood that such equivalent embodiments form part of this invention.

Claims (19)

1. Citrate salt CHARACTERIZED by the fact that it is 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6) .1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene. 2. Salt, according to claim 1, CHARACTERIZED by the fact that the salt is crystalline. 3. Salt, according to claim 1 or 2, CHARACTERIZED by the fact that salt is salt 1:1. 4. Salt, according to any one of claims 1 to 3, CHARACTERIZED in that it shows in X-ray diffraction a peak in the 2theta scale at 22.4°±0.5°. 5. Salt, according to claim 4, CHARACTERIZED by the fact that it also shows peaks on the 2theta scale in X-ray diffraction at 10.2°±0.5° and 15.7°±0.5°. 6. Salt according to any one of claims 1 to 5, CHARACTERIZED in that it shows in X-ray diffraction at least four peaks on the 2theta scale selected from the group consisting of 7.8°±0.5°, 10.2°±0.5°, 14.2°±0.5°, 15.7°±0.5°, 16.8°±0.5°, 21.4°±0.5° and 22.4°±0.5°. 7. Salt according to claim 6, CHARACTERIZED in that it shows in X-ray diffraction at least 6 peaks on the 2theta scale selected from the group consisting of 7.8°±0.5°, 10.2° ±0.5°, 14.2°±0.5°, 15.7°±0.5°, 16.8°±0.5°, 21.4°±0.5° and 22.4° ±0.5°. 8. Salt, according to claim 6, CHARACTERIZED by the fact that it shows in X-ray diffraction peaks on the 2theta scale at 7.8°±0.5°, 10.2°±0.5°, 14.2 °±0.5°, 15.7°±0.5°, 16.8°±0.5°, 21.4°±0.5° and 22.4°±0.5°. 9. Salt, according to claim 8, CHARACTERIZED by the fact that it also shows in X-ray diffraction peaks on the 2theta scale at 10.9°±0.5°, 17.1°±0.5°, 23, 3°±0.5°, 25.1°±0.5°, 25.8°±0.5° and 27.5°±0.5°. 10. Salt, according to claim 9, CHARACTERIZED by the fact that it also shows in X-ray diffraction peaks on the 2theta scale at 7.2°±0.5°, 17.6°±0.5°, 18, 5°±0.5°, 18.7°±0.5°, 20.7°±0.5°, 23.1°±0.5°, 24.2°±0.5°, 26, 2°±0.5°, 26.9°±0.5°, 28.7°±0.5°, 29.3°±0.5°, 31.0°±0.5°, 32, 4°±0.5°, 37.3°±0.5°, 38.6°±0.5°, 39.9°±0.5° and 41.6°±0.5°. 11. Pharmaceutical composition CHARACTERIZED in that it comprises a salt as defined in any one of claims 1 to 10. 12. Use of a salt, as defined in any one of claims 1 to 10, CHARACTERIZED in that it is in the manufacture of a medicament for the prevention or treatment of a proliferative disorder. 13. Use according to claim 12, CHARACTERIZED by the fact that the proliferative disorder is cancer. 14. Use according to claim 13, CHARACTERIZED by the fact that the cancer is glioblastoma multiforme, chronic myelomonocytic leukemia or Hodgkin's disease. 15. Use, according to claim 13, CHARACTERIZED by the fact that the cancer is glioblastoma multiforme. 16. Use, according to claim 13, CHARACTERIZED by the fact that the cancer is chronic myelomonocytic leukemia. 17. Use according to claim 13, CHARACTERIZED by the fact that the cancer is Hodgkin's disease. 18. Use, according to claim 12, CHARACTERIZED by the fact that the proliferative disorder is myeloproliferative disorder. 19. Use according to claim 18, CHARACTERIZED by the fact that the myeloproliferative disorder is chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia or chronic myeloid leukemia.

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